Aurones as selective pde inhibitors and their use in neurological conditions and disorders

Abstract

The invention relates to aurones and extracts comprising them useful in the prophylactic and/or therapeutic treatment of an animal (including a human) with a phosphodiesterase (PDE) dependent disease or condition of the central nervous system, as well as methods, uses and other inventions related thereto.

1 . A compound of the formula I, 
       
         
           
           
               
               
           
         
       
       wherein each of R 1  to R 9  is, independently of the others, H, hydroxy, fluoro, chloro, bromo, iodo, C 1 -C 8 -alkyl, C 2 -C g -alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 -cycloalkyl, phenyloxy, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy, benzoyl or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms, where alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, alkoxy, alkanoyloxy and benzoyl can be unsubstituted or substituted by one, two or three substituents selected independently of each other from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , OCH 2 CH 3 , OCOCH 3 , —CH 3 , —CHO, and CO 2 H, or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms, preferably with the proviso that if R 1 , R 3  and R 7  each are bound via an oxygen, R 2 , R 4 , R 5  and R 9  each are hydrogen and one of R 6  and R 8  is bound via an oxygen, then the other of R 6  and R 8  has one of the meanings mentioned above other than H;
 where one of R 1  to R 9  may, in addition, be a substitutent of the subformula IA 
 
       
         
           
           
               
               
           
         
       
       wherein one of R 1 ′ to R 9 ′ forms the bond to the rest of the molecule in formula I, while the others are, independently of each other, H, hydroxy, fluoro, chloro, bromo, iodo, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 -cycloalkyl, phenyloxy, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy, benzoyl or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms, where alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, alkoxy, alkanoyloxy and benzoyl can be unsubstituted or substituted by one, two or three substituents selected independently of each other from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , —OCH 2 CH 3 , —OCOCH 3 , —CHO, and —CO 2 H;
 or two adjacent moieties of R 1  to R 9  and of R 1 ′ to R 9 ′ together form a —O—CH 2 —O— or a —O—CH 2 —CH 2 —O— bridge, thus forming with the two atoms to which they are bound a ring, while the other moieties are independently selected from those mentioned above; 
 in formula I either bond a and bond c each are a double bond, or bonds b and bond d each are a double bond, respectively; 
 and, if present, in subformula IA either bond a′ and bond c′ each are a double bond, or bonds b′ and bond d′ each are a double bond, respectively; 
 where the double bonds in formula I and, if present, subformula IA, may also be in tautomeric equilibrium; 
 X is hydrogen, oxo, hydroxy, C 1 -C 8 -alkoxy, especially methoxy, C 1 -C 8 -alkanoyloxy, especially acetyloxy, benzoyloxy or 3,4,5-trihydroxybenzoyloxy, or, if bonds a and c are double bonds in formula I and Y is oxo, can also be a moiety of the subformula IB, 
 
       
         
           
           
               
               
           
         
       
       wherein the waved line indicates the end of the bond where said moiety of the subformula IB is bound to the rest of the molecule of formula I and wherein
 Y* is oxo and 
 R 1 * to R 9 * are, independently of each other, H, hydroxy, fluoro, chloro, bromo, iodo, C 1 -C 8 -alkyl, phenyloxy, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy, benzoyl or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms; 
 and Y is oxo, hydroxy or C 1 -C 8 -alkoxy; 
 a mixture of two or more compounds of the formula I, and/or an extract comprising one or more compounds of the formula I, for use in the prophylactic and/or therapeutic treatment of an animal with a phosphodiesterase (PDE) dependent disease or condition of the central nervous system; 
 where the compounds of the formula I may be present in free form, in the form of a pharmaceutically and/or nutraceutically acceptable salt, in the form of a tautomer, in the form of an ester and/or in the form of a solvate. 
 
     
     
         2 . A compound for use of the formula I, mixture of compounds of the formula I or extract of the formula I according to  claim 1 , wherein
 Y is oxo,   X is H, hydroxy, methoxy, acetoxy, benzoyloxy or 3,4,5-trihydroxybenzoyloxy,   the bonds a and c are double bonds, respectively, the bonds b and d are single bonds, respectively,   where the compounds of the formula I may be present in free form, in the form of a pharmaceutically and/or nutraceutically acceptable salt, in the form of a tautomer, in the form of an ester and/or in the form of a solvate.   
     
     
         3 . A compound for use of the formula I, mixture of compounds of the formula I or extract of the formula I according to  claim 1 , wherein
 each of R 1  to R 9  is, independently of the others, H, hydroxy, chloro, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy or benzoyl with the proviso that if R 1 , R 3  and R 7  each are hydroxyl, R 2 , R 4 , R 5  and R 9  each are hydrogen and one of R 6  and R 8  is hydroxy, then the other of R 6  and R 8  has one of the meanings mentioned above other than H;   Y is oxo, and   X is H, hydroxy, methoxy, acetoxy, benzoyloxy or 3,4,5-trihydroxybenzoyloxy,   the bonds a and c are double bonds, respectively, the bonds b and d are single bonds,   where the compounds of the formula I may be present in free form, in the form of a pharmaceutically and/or nutraceutically acceptable salt, in the form of a tautomer, in the form of an ester and/or in the form of a solvate.   
     
     
         4 . A compound of the formula I, mixture of compounds of the formula I and/or extract of the formula I for use according to  claim 1 , where the compound(s) of the formula I is or are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         where the compound(s) may be present in free form, in the form of a tautomer, in the form of an ester and/or in the form of a solvate. 
       
     
     
         5 . An extract comprising one or more compounds of the formula I in free or any other form mentioned for use according to  claim 1  which is obtained from  Smilax myosotiflora , especially from the roots. 
     
     
         6 . An extraction and purification or at least enrichment process for obtaining a compounds or an extract according to  claim 1 , comprising
 an extraction step from a plant or plant parts, where the plant is of the Genus  Smilax , and   a first liquid/liquid separation step under acidic conditions, followed by   a subsequent second liquid/liquid extraction of the material found in the less polar phase of the first extraction step, preferably under neutral to slightly alkaline conditions,   where preferably   said extraction and said first liquid/liquid separation step takes place under acidic conditions at a pH of about 2 to about 4.5, more preferably about 2 to about 3, most preferably at a pH of about 2a followed by said second liquid/liquid extraction step performed at a pH of about 7 or larger, preferably about 7 to about 9, and a most preferably a pH of 7.4 to 7.6.   
     
     
         7 . A compound of the formula I, mixture of compounds of the formula I and/or extract for use obtainable according to the process according to  claim 6 , wherein the compound or compounds according to formula I are present in an amount of 10 or more % by weight. 
     
     
         8 . A compound of the formula I, mixture of compounds of the formula I and/or extract for use obtainable according to the process according to  claim 6 , wherein the compound or compounds according to formula I are present in an amount of 30 or more % by weight. 
     
     
         9 . A compound of the formula I, mixture of compounds of the formula I and/or extract for use obtainable according to the process according to  claim 6 , wherein the compound or compounds according to formula I are present in an amount of 50% or more by weight. 
     
     
         10 . A compound of the formula I, mixture of compounds of the formula I and/or extract for use obtainable according to the process according to  claim 6 , wherein the compound or compounds according to formula I are present in an amount of 80 to 100% by weight. 
     
     
         11 . An extract from plants of the genus  Smilax  obtainable according to the method of  claim 6 , comprising a compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein each of R 1  to R 9  is, independently of the others, H, hydroxy, fluoro, chloro, bromo, iodo, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 -cycloalkyl, phenyloxy, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy, benzoyl or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms, where alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, alkoxy, alkanoyloxy and benzoyl can be unsubstituted or substituted by one, two or three substituents selected independently of each other from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , —OCH 2 CH 3 , —OCOCH 3 , —CH 3 , —CHO, and —CO 2 H, or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms;
 where one of R 1  to R 9  may, in addition, be a substitutent of the subformula IA 
 
       
         
           
           
               
               
           
         
       
       wherein one of R 1 ′ to R 9 ′ forms the bond to the rest of the molecule in formula I, while the others are, independently of each other, H, hydroxy, fluoro, chloro, bromo, iodo, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 3 -C 10 -cycloalkyl, phenyloxy, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy, benzoyl or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms, where alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, alkoxy, alkanoyloxy and benzoyl can be unsubstituted or substituted by one, two or three substituents selected independently of each other from the group consisting of —F, —Cl, —Br, —I, —OH, —OCH 3 , —OCH 2 CH 3 , —OCOCH 3 , —CHO, and —CO 2 H;
 or two adjacent moieties of R 1  to R 9  and of R 1 ′ to R 9 ′ together form a —O—CH 2 —O— or a —O—CH 2 —CH 2 —O— bridge, thus forming with the two atoms to which they are bound a ring, while the other moieties are independently selected from those mentioned above; 
 in formula I either bond a and bond c each are a double bond, or bonds b and bond d each are a double bond, respectively; 
 and, if present, in subformula IA either bond a′ and bond c′ each are a double bond, or bonds b′ and bond d′ each are a double bond, respectively; 
 where the double bonds in formula I and, if present, subformula IA, may also be in tautomeric equilibrium (of a beta di-keto system); 
 X is hydrogen, oxo, hydroxy, C 1 -C 8 -alkoxy, especially methoxy, C 1 -C 8 -alkanoyloxy, especially acetyloxy, benzoyloxy or 3,4,5-trihydroxybenzoyloxy, or, if bonds a and c are double bonds in formula I and Y is oxo, can also be a moiety of the subformula IB, 
 
       
         
           
           
               
               
           
         
       
       wherein the waved line indicates the end of the bond where said moiety of the subformula IB is bound to the rest of the molecule of formula I and wherein
 Y* is oxo and 
 R 1 * to R 9 * are, independently of each other, H, hydroxy, fluoro, chloro, bromo, iodo, C 1 -C 8 -alkyl, phenyloxy, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy, benzoyl or the radical of a C 5 -C 12 -carbohydrate bound via one of its oxygen atoms; 
 and Y is oxo, hydroxy or C 1 -C 8 -alkoxy; 
 a mixture of two or more such compounds of the formula I, and/or an extract comprising one or more such compounds of the formula I; 
 where the compounds of the formula I may be present in free form, in the form of a pharmaceutically and/or nutraceutically acceptable salt, in the form of a tautomer, in the form of an ester and/or in the form of a solvate. 
 
     
     
         12 . A compound of the formula I, mixture of compounds of the formula I or extract according to  claim 11 , wherein
 Y is oxo,   X is H, hydroxy, methoxy, acetoxy, benzoyloxy or 3,4,5-trihydroxybenzoyloxy,   the bonds a and c are double bonds, respectively, the bonds b and d are single bonds, respectively, where the compounds of the formula I may be present in free form, in the form of a pharmaceutically and/or nutraceutically acceptable salt, in the form of a tautomer, in the form of an ester and/or in the form of a solvate.   
     
     
         13 . A compound of the formula I, mixture of compounds of the formula I or extract according to  claim 11 , wherein
 each of R 1  to R 9  is, independently of the others, H, hydroxy, chloro, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 9 -alkanoyloxy or benzoyl with the proviso that if R 1 , R 3  and R 7  each are hydroxyl, R 2 , R 4 , R 5  and R 9  each are hydrogen and one of R 6  and R 8  is hydroxy, then the other of R 6  and R 8  has one of the meanings mentioned above other than H;   Y is oxo, and   X is H, hydroxy, methoxy, acetoxy, benzoyloxy or 3,4,5-trihydroxybenzoyloxy,   the bonds a and c are double bonds, respectively, the bonds b and d are single bonds,   where the compounds of the formula I may be present in free form, in the form of a pharmaceutically and/or nutraceutically acceptable salt, in the form of a tautomer, in the form of an ester and/or in the form of a solvate.   
     
     
         14 . The extract of  claim 11 , obtained from  Smilax myosotiflora.    
     
     
         15 . A pharmaceutical or nutraceutical composition, comprising an extract according to  claim 11  and at least one pharmaceutically or nutraceutically acceptable carrier material. 
     
     
         16 . The use of an extract according to  claim 11  for the manufacture of a medicament for the prophylactic and/or therapeutic treatment of a PDE dependent disease or condition of the central nervous system. 
     
     
         17 . A method of prophylactically and/or therapeutically treating an animal, especially a human in need of such treatment, of using a compound of the formula I, presumed to suffer in future or suffering from a phosphodiesterase (PDE) dependent disease or condition of the central nervous system, comprising administering to said animal or human an effective amount of an extract according to  claim 11 . 
     
     
         18 . A pharmaceutical composition or a nutraceutical comprising a compound of the formula I, a mixture of compounds of the formula I or an extract according to  claim 1  for use in the prophylactic and/or therapeutic treatment of an animal with a phosphodiesterase (PDE) dependent symptom or condition of the central nervous system, together with at least one pharmaceutically or nutraceutically acceptable carrier material. 
     
     
         19 . The composition according to  claim 18 , where the compound(s) of formula I are present in an amount of 0.001 to 100% by weight. e.g. from 0.1 to 50% by weight. 
     
     
         20 . The composition according to  claim 18 , where the compound(s) of formula I are present in an amount of 0.1 to 50% by weight. 
     
     
         21 . A method of prophylactically and/or therapeutically treating an animal, especially a human in need of such treatment, of using a compound of the formula I, presumed to suffer in future or suffering from a phosphodiesterase (PDE) dependent disease or condition of the central nervous system, comprising administering to said animal or human an effective amount of a compound of the formula I, a compound mixture or an extract according to  claim 1  in free or other forms mentioned therein. 
     
     
         22 . The use of a compound of the formula I, or a mixture of compounds of the formula I, or an extract comprising one or more compounds of the formula I, as defined in  claim 1  in free or other forms mentioned therein, as active ingredient for the manufacture of a medicament or nutraceutical or food supplement for the treatment of a PDE dependent disease or condition of the central nervous system. 
     
     
         23 . The use of a compound of the formula I, or a mixture of compounds of the formula I, or an extract comprising one or more compounds of the formula I, as defined in  claim 1  in free or other forms mentioned therein, as active ingredient in the treatment of a PDE dependent disease or condition of the central nervous system. 
     
     
         24 . The compound, compound mixture or extract in free or any other form mentioned according to  claim 1 , where the PDE dependent disease or condition of the central nervous system is a neurodegenerative disease. 
     
     
         25 . The compound, compound mixture or extract in free or any other form mentioned according to  claim 1  where the PDE dependent disease or condition of the central nervous system is Parkinson's disease, Alzheimer's disease, age related dementia or dementia in general. 
     
     
         26 . The compound, compound mixture or extract in free or any other form mentioned according to  claim 1  where the PDE dependent disease or condition of the central nervous system is neurological trauma including brain or central nervous system trauma and/or recovery therefrom, and/or ischemia of the central and/or peripheral nervous systems. 
     
     
         27 . The compound, compound mixture or extract in free or any other form mentioned according to  claim 1 , where the PDE dependent disease or condition of the central nervous system is depression, anxiety, psychosis, cognitive dysfunction, mental dysfuntion, a learning disorder, and memory disorder. 
     
     
         28 . The compound, compound mixture or extract in free or any other form mentioned according to  claim 1 , where the PDE dependent disease or condition of the central nervous system is one that requires improvement of cognitive outcomes and mood disorders. 
     
     
         29 . The compound, compound mixture or extract in free or any other form mentioned according to  claim 1 , where the PDE dependent disease or condition of the central nervous system is one that requires enhancement of cognition. 
     
     
         30 . The pharmaceutical composition or a nutraceutical comprising a compound of the formula I, a mixture of compounds of the formula I or an extract according to  claim 1  for wherein the composition is suitable for administration intravenously, intraperitoneally, subcutaneously, intramuscularly, intrathecally, orally, rectally, topically, or by inhalation. 
     
     
         31 . The compound, compound mixture or extract in free or any other form mentioned according to  claim 1  where the PDE dependent disease of condition of the central nervous system is one that requires modulating, such as protecting or stabilizing, neuronal and glial function and CNS homeostasis.